The selective conversion of one functional group in a multifunctional feed substrate has been an area of continuous high interest throughout the chemical, pharmaceutical and agrochemical industry. In particular, halogen atoms are often incorporated next to other functional groups in active ingredients or in precursors of those active ingredients.
The objective of high selectivity has often been rather elusive, because most processes are prone to side reactions leading to significant amounts of by-products.
A variety of methods have been attempted in order to increase the selectivity of metal catalysed reductive aminations of one functional group in the presence of one or more halogen atoms elsewhere in the substrate molecule. A selection of such methods is discussed in WO 2015/032653 A1, which also provides literature references containing further details.
One method involves the addition of modifiers to the reaction mixture or working into alternative reaction media. In this regard, reference is made to U.S. Pat. Nos. 5,011,996, 6,429,335 B1, and US 2007/0078282 A1.
Other chemical pathways to obtain particularly valuable polyfunctional products containing halogens have also been explored. In this regard, reference is made to WO 2014/135508 A1, WO 2014/202436 A1, and WO 2015/032653 A.
The copending patent application PCT/EP2015/075734, filed on 4 Nov. 2015, discloses reductive amination reaction of 2-chloro-benzyaldehyde with DMA (dimethyl amine) to form 2-chloro-benzyl dimethyl amine (2-Cl-BDMA).
The inventors have however found that the reductive amination reactions using metal based catalysts as disclosed in the prior art may still suffer from the drawback that by-products may be formed during the reaction. The inventors have further found that particular by-products appear to have low solubility in the reaction mixture, even in significant presence of a solvent. The amount of at least one particular by-product formed can therefore rapidly exceed its solubility limit, and a precipitate may be formed. The amount of precipitate formed is small and may readily be overlooked in laboratory scale experiments, but in an industrial environment this amount may prove to be largely sufficient to cause operational problems, such as clogging filters and/or piping. In addition, the particular by-product appears act to as a poison for the heterogeneous catalyst, rapidly decreasing not only the selectivity to the desired reaction product, but also the activity to a degree that the life time of the catalyst can become unacceptably short.
There accordingly remains a need for a process to perform reductive amination reactions of halogenated substrates using a metal based catalyst in high selectivity and in which process the amount of this at least one particular type of by-product formed is reduced.
The present invention aims to obviate or at least mitigate the above described problem and/or to provide improvements generally.